Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK

Publication date: Available online 17 December 2018Source: NeuronAuthor(s): Perrine Royal, Alba Andres-Bilbe, Pablo Ávalos Prado, Clément Verkest, Brigitte Wdziekonski, Sébastien Schaub, Anne Baron, Florian Lesage, Xavier Gasull, Joshua Levitz, Guillaume SandozSummaryIt is often unclear why some genetic mutations to a given gene contribute to neurological disorders and others do not. For instance, two mutations have previously been found to produce a dominant negative for TRESK, a two-pore-domain K+ channel implicated in migraine: TRESK-MT, a 2-bp frameshift mutation, and TRESK-C110R. Both mutants inhibit TRESK, but only TRESK-MT increases sensory neuron excitability and is linked to migraine. Here, we identify a new mechanism, termed frameshift mutation-induced alternative translation initiation (fsATI), that may explain why only TRESK-MT is associated with migraine. fsATI leads to the production of a second protein fragment, TRESK-MT2, which co-assembles with and inhibits TREK1 and TREK2, two other two-pore-domain K+ channels, to increase trigeminal sensory neuron excitability, leading to a migraine-like phenotype in rodents. These findings identify TREK1 and TREK2 as potential molecular targets in migraine and suggest that fsATI should be considered as a distinct class of mutations.Graphical Abstract

Source: Neuron - December 18, 2018 Category: Neuroscience Source Type: research